In the absence of excessive alcohol consumption, increased levels of fat in the liver (>5%) are diagnosed as non-alcoholic fatty liver (NAFL). It has been shown that NAFL is strongly associated with impairments in metabolic health such as hepatic and whole-body insulin resistance. Insulin resistance is seen as the earliest hallmark in the development of type 2 diabetes.

Insulin has two main effects on the liver: suppressing endogenous glucose production (EGP) and increasing glucose uptake. While the former has been extensively studied and is known to be impaired in NAFL, no studies have yet examined whether insulin-stimulated hepatic glucose uptake is affected by NAFL.

Recent methodological developments allow us to visualize and quantify glucose uptake in any given tissue using dynamic Positron Emission Tomography (PET) with 18Fluorinated glucose tracer (FDG) during insulin stimulation.

In the present study, we will in a first instance optimize the insulin-stimulated whole-body PET protocol and apply the dose as reported in the literature 4 megabequerels per kg of body weight (MBq/kg) (±8 mSv) in the first three subjects. It will then be evaluated whether the dose can be decreased in the remaining measurements. Another twelve individuals will then undergo the optimized dynamic PET protocol to assess insulin-stimulated hepatic glucose together with whole-body glucose uptake measures. Liver fat content and composition will be assessed by proton magnetic resonance spectroscopy (1H-MRS). Fasted De Novo Lipogenesis (DNL) will also be measured by deuterated water. Additionally, a two-step clamp will be performed to measure whole-body insulin sensitivity and insulin-stimulated suppression of EGP. The identification of the contributing factors to insulin resistance during the development of NAFL is crucial in order to develop more effective strategies for the prevention and treatment of metabolic disorders.

Objective:

To determine the association between insulin-stimulated hepatic glucose uptake measured by dynamic PET and liver fat content in overweight/obese subjects.

Inclusion Criteria:

• Caucasian (people will be excluded when having a ≥50% racial African/Asian background)
• Male or postmenopausal female
• Aged 45-75 years at start of the study
• Body mass index (BMI) 27 - 38 kg/m2
• Stable dietary habits (no weight loss or gain >3kg in the past 3 months)
• Sedentary lifestyle (not more than 2 hours of vigorous exercise per week)

Exclusion Criteria:

• Type 2 diabetes (fasted blood glucose > 7 mmol/L)
• Any condition or medical history that would in the investigator's or dependent physician's opinion interfere with the study, with study outcomes or increase the risk of the study procedures
• Alcohol consumption of >2 servings per day
• Smoking
• Low Hb (men: <8.6 mmol/L; women <7.4 mmol/L)
• Use of medication known to interfere with the safety of study procedures
• Use of medication known to increase liver fat, like for instance corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall).
• Subjects receiving thiazolidinediones (glitazones [pioglitazone, rosiglitazone]).
• Participation in research or medical examination that included PET/CT scanning in the last 3 months
• Contra-indication for MRI

A total of 15 healthy overweight/obese males and post-menopausal females (45-75 years, BMI 27-38 kg/m2) will participate in the study. Recruitment of participants will be performed in Maastricht and surroundings, by means of posters in public spaces (supermarkets, hospital, pharmacy, general practitioners), advertisements in local newspapers (e.g. Dagblad de Limburger and EenLokaal) and on the internet (e.g. digiprik.nl, proefbunny.nl and facebook.nl). Participants from previous studies will be contacted as well in case they provided written consent for this. To increase recruitment efficiency, potential participants can register at a mailing list. With this list, the researcher can approach individuals who showed interest in participating scientific research.